Abstinence from cocaine and sucrose self-administration reveals altered mesocorticolimbic circuit connectivity by resting state MRI.

Previous preclinical studies have emphasized that drugs of abuse, through actions within and between mesocorticolimbic (MCL) regions, usurp learning and memory processes normally involved in the pursuit of natural rewards. To distinguish MCL circuit pathobiological neuroadaptations that accompany addiction from general learning processes associated with natural reward, we trained two groups of rats to self-administer either cocaine (IV) or sucrose (orally) followed by an identically enforced 30 day abstinence period. These procedures are known to induce behavioral changes and neuroadaptations. A third group of sedentary animals served as a negative control group for general handling effects. We examined low-frequency spontaneous fluctuations in the functional magnetic resonance imaging (fMRI) signal, known as resting-state functional connectivity (rsFC), as a measure of intrinsic neurobiological interactions between brain regions. Decreased rsFC was seen in the cocaine-SA compared with both sucrose-SA and housing control groups between prelimbic (PrL) cortex and entopeduncular nucleus and between nucleus accumbens core (AcbC) and dorsomedial prefrontal cortex (dmPFC). Moreover, individual differences in cocaine SA escalation predicted connectivity strength only in the Acb-dmPFC circuit. These data provide evidence of fronto-striatal plasticity across the addiction trajectory, which are consistent with Acb-PFC hypoactivity seen in abstinent human drug addicts, indicating potential circuit level biomarkers that may inform therapeutic interventions. They further suggest that available data from cross-sectional human studies may reflect the consequence of rather a predispositional predecessor to their dependence.

Temporary disruption of the rat blood-brain barrier with a monoclonal antibody: a novel method for dynamic manganese-enhanced MRI.

Manganese (Mn(2+)) has limited permeability through the blood-brain barrier (BBB). Opening the BBB such that a sufficient amount of Mn(2+) enters the extracellular space is a critical step for dynamic manganese-enhanced magnetic resonance imaging (ME-MRI) experiments. The traditional BBB opening method uses intracarotid hyperosmolar stress which results in suboptimal BBB opening, and practically is limited to nonsurvival experiments due to substantial surgical trauma. In the present ME-MRI study, we investigate the feasibility of opening the BBB with an antibody that targets the endothelial barrier antigen (EBA) specifically expressed by rat endothelial cells. Results demonstrate that intravenous infusion of the anti-EBA agent SMI-71 leads to BBB disruption of the whole brain as detected by ME-MRI and confirmed by Evans blue dye staining. Physiologically, injection of SMI-71 leads to a hypertensive response followed by a sustained hypotensive response in animals anesthetized with urethane alone. Incorporating isoflurane partially mitigated both pressor responses. In general, BBB disruption via intravenous infusion of SMI-71 is straightforward and obviates technical difficulties associated with intracarotid hyperosmolar stress, opening new possibilities for in vivo neuroimaging with ME-MRI. The data also suggest that ME-MRI may be used as an imaging method to assess BBB integrity complementary to the Evans blue dye method, a classical but highly invasive technique, permitting longitudinal assessment of the integrity of the BBB on the same animal.

NIDA522131, a new radioligand for imaging extrathalamic nicotinic acetylcholine receptors: in vitro and in vivo evaluation.

A novel radioligand, 6-chloro-3-((2-(S)-azetidinyl)methoxy)-5-(2-fluoropyridin-4-yl)pyridine (NIDA522131), for imaging extrathalamic nicotinic acetylcholine receptors (nAChRs) was characterized in vitro and in vivo using positron emission tomography. The K(d) and T(1/2) of dissociation of NIDA522131 binding measured at 37 degrees C in vitro were 4.9 +/- 0.4 pmol/L and 81 +/- 5 min, respectively. The patterns of radioactivity distribution in monkey brain in vivo was similar to that of 2-[(18)F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2FA), a radioligand that has been successfully used in humans, and matched the alpha(4)beta(2)* nAChRs distribution. Comparison between [(18)F]NIDA522131 and 2FA demonstrated better in vivo binding properties of the new radioligand and substantially greater radioactivity accumulation in brain. Consistent with [(18)F]NIDA522131 elevated affinity for nAChRs and its increased lipophilicity, both, the total and non-displaceable distribution volumes were substantially higher than those of 2FA. Estimated binding potential values in different brain regions, characterizing the specificity of receptor binding, were 3-4 fold higher for [(18)F]NIDA522131 than those of 2FA. Pharmacological evaluation in mice demonstrated a toxicity that was comparable to 2FA and is in agreement with a 2300 fold higher affinity at alpha(4)beta(2)* versus alpha(3)beta(4)* nAChRs. These results suggest that [(18)F]NIDA522131 is a promising positron emission tomography radioligand for studying extrathalamic nAChR in humans.

Evaluation of 5-(2-(4-pyridinyl)vinyl)-6-chloro-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine and its analogues as PET radioligands for imaging nicotinic acetylcholine receptors.

A novel series of compounds derived from the high-affinity nicotinic acetylcholine receptor (nAChR) ligand, 5-(2-(4-pyridinyl)vinyl)-6-chloro-3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine (Me-p-PVC), originally developed by Abbott Laboratories, was characterized in vitro in nAChR binding assays at 37 degrees C to show K(i) values in the range of 9-611 pm. Several compounds of this series were radiolabeled with (11)C and evaluated in vivo in mice and monkeys as potential candidates for PET imaging of nAChRs. [(11)C]Me-p-PVC (K(i) =56 pm at 37 degrees C; logD = 1.6) was identified as a radioligand suitable for the in vivo imaging of the alpha 4 beta 2* nAChR subtype. Compared with 2-[(18)F]FA, a PET radioligand that has been successfully used in humans and is characterized by a slow kinetic of brain distribution, [(11)C]Me-p-PVC is more lipophilic. As a result, [(11)C]Me-p-PVC accumulated in the brain more rapidly than 2-[(18)F]FA. Pharmacological evaluation of Me-p-PVC in mice demonstrated that the toxicity of this compound was comparable with or lower than that of 2-FA. Taken together, these results suggest that [(11)C]Me-p-PVC is a promising PET radioligand for studying nAChR occupancy by endogenous and exogenous ligands in the brain in vivo.